The observed increase in detectable clonal mosaicism late in life may be due to a change in the frequency with which chromosomal anomalies occur (i.e. increased somatic mutation rate) and/or their ability to form large clones (i.e. clonal expansion). Previous work has shown that the occurrence of chromosomal anomalies (rearrangements and aneuploidies) during cell division increases with age in cultured lymphocytes and fibroblasts30,31, that DNA damage accumulates with age in mouse hematopoietic stem cells32, and that mitotic recombination (leading to uniparental disomy) increases with replicative age in yeast33. This apparent increase in somatic mutation may result from age-related decline in genomic maintenance mechanisms (such as telomere attrition34). Clonal expansion of cells containing chromosomal anomalies could be due to either positive selection or to random changes in the frequencies of hematopoietic stem cell descendants. In principle, stem cell senescence and age-related decline in replicative function35 could result in a decrease in the effective population size of stem cells, leading to shifts in clonal composition analogous to random drift in small populations of individuals36. However, analyses of the clonal composition of blood
